Abstract C122: Phase 1b relative bioavailability (BA) study of enteric coated tablet (ECT) in reference to powder in capsule (PIC) formulation of the investigational drug alisertib (MLN8237), an Aurora A Kinase (AAK) inhibitor, in patients with advanced nonhematologic malignancies.

Abstract

Abstract Background: The investigational drug alisertib (MLN8237) is an orally available, selective AAK inhibitor. Early clinical studies used a PIC formulation; an ECT formulation was recently developed. Here we present relative BA results of ECT referenced to PIC designed to bridge transition to ECT in MLN8237 clinical development. Methods: Eligible patients were age ≥18 years with advanced solid tumors and ECOG PS 0–1. Dose-escalation cohorts received alisertib 10 mg BID (N=1), and 20 mg BID (N=1), before formal relative BA evaluation at 40 mg BID, in a 7-day schedule followed by 14 days' rest (21-day cycles). Patients received MLN8237 40 mg BID as either ECT or PIC in a 2-cycle, 2-way cross-over design. Pharmacokinetic (PK) sampling was performed on Day 7 of cycles 1 and 2 to characterize steady-state PK of alisertib formulated as ECT or PIC for relative BA analysis. PK was also evaluated on Day 1 of ECT dosing. Results: 22 patients were included (N=1 each at 10 and 20 mg BID; N=20 at 40 mg BID); 55% were male, 90% were white, and median age was 56 years. 14 patients were evaluable for relative BA analysis. Following BID oral dosing, absorption was fast (median Tmax ∼2.5 hours for ECT; ∼2 hours for PIC). Relative BA of ECT referenced to PIC was 90% (90% CI: 74.4, 108.8). Steady-state Cmax following ECT was 82% of that from PIC (90% CI: 69.9, 95.5). Mean accumulation ratio of ECT BID was ∼2.8-fold; mean peak-to-trough ratio was ∼2.5. The range of dose-normalized exposures following ECT was within the corresponding range observed with PIC, which has previously been associated with favorable pharmacodynamic effects (Dees et al. Abstract 3010; Cervantes et al. Abstract 3031, J Clin Oncol 2010;28:15s). Conclusions: Systemic exposures following administration of ECT and PIC formulations of alisertib are generally similar, supporting transition from PIC to ECT in clinical development. Taken together with PK, pharmacodynamics, and antitumor activity from other trials, these data indicate that the ECT formulation of alisertib can provide exposures needed for clinically relevant bioactivity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C122.